Membrane Fusion‐Mediated Cytosolic Delivery of Threose Nucleic Acids via Homotypic Nanoparticles Overcomes Drug Resistance in Triple‐Negative Breast Cancer

ABSTRACT Triple‐negative breast cancer (TNBC) remains lethal due to its aggressive molecular heterogeneity and drug resistance. We report a biomimetic nanoplatform (PLL/TNA AKT2 @CM NPs) integrating biostable threose nucleic acid (TNA) with a donor‐derived cell membranes (CMs) “cloak” for subtype‐specific therapy. By complexing TNA AKT2 antisense oligonucleotides with poly‐L‐lysine (PLL) and coating them with TNBS‐subtype membranes (MDA‐MB‐468 or MDA‐MB‐231), we achieve potent homotypic affinity. PLL/TNA AKT2 @468CM NPs exhibited significant enhanced uptake in donor‐matched basal‐like 1 cells compared to heterotypic TNBC, non‐TNBC and normal epithelial cells. Mechanistically, these nanoparticles internalize via a rapid membrane‐fusion, bypassing endosomal entrapment for direct cytosolic delivery. This facilitates robust silencing of the AKT2 oncogene, achieving a  ∼ 70% protein knockdown and outperforming conventional transfection reagents. In a drug‐resistant MDA‐MB‐468 xenografts, systemic administration led to superior tumor accumulation, effective AKT2 knockdown, and significant tumor regression via the p21/Caspase‐3 apoptotic axis, without systemic toxicity. This versatile “plug‐and‐play” strategy addresses tumor heterogeneity and endosomal sequestration, providing a transformative paradigm for targeted nucleic acid delivery in refractory cancers.